Comparative Application of the Fluctuation Test to the data of Morbidity by COVID-19 in United States of America, United Kingdom, Taiwan and China 2020-2023 (preprint)

In this work the Luria and Delbruck Fluctuation Test was comparatively applied to the data of Morbidity by COVID-19 in the United States of America (USA), United Kingdom (UK), Taiwan and China from 2020 to 2023. Three types of data were used: es.statista.com, datosmacro.expansion.com and larepublica.co without modification, but trying to avoid and justify the anomalies and inconsistencies observed. The methods originally used to establish the interactions of two populations were evaluated: the viral population with that of its host and the drift of both organisms. Only the interactive fluctuations of the weekly Variance of daily increase of Cases (Morbidity) were studied. The results showed that the Fluctuation Test is applicable to the selected data from USA, UK, Taiwan and China and other data from several countries used as controls. The study was separated into two approaches: First, comparison of the total or partial logarithmic profile of fluctuations of Variance of Cases (Morbidity) of USA, UK, Taiwan and China. Second, comparison of the values of the first fluctuation of Variance of Cases (Morbidity) in the boreal winter of 2020 for USA, UK, Taiwan, China and several countries used as controls. The results obtained for Morbidity demonstrate that USA and UK present a similar bimodal profile. China shows an inverted profile and Taiwan shows an intermediate profile between both tendencies. However, it was possible to detect some anomalies and uncertainties that were possibly derived from inconsistencies in the original data. Only USA shows a value of the first fluctuation comparable to the order of magnitude of the value of the first fluctuation of the Variance of Cases of China, in the northern winter of 2020. In the First Approach USA, UK and China had two important fluctuations: the first in the northern winter of 2020 before week 16 and the second at the beginning of northern winter of 2022, more than 100 weeks later. Taiwan showed only the latter. This latest fluctuation coincides with two events: the possible achievement of herd immunity and the emergence of Omicron variant. In this work we have evaluated whether this coincidence is casual or causal. The results obtained in the Second Approach aim to confirm the hypothesis of the animal origin of the first variant of SARS CoV-2.

Mapping immunodominant sites on the MERS-CoV spike glycoprotein targeted by infection-elicited antibodies in humans (preprint)

Middle-East respiratory syndrome coronavirus (MERS-CoV) first emerged in 2012 and causes human infections in endemic regions. Most vaccines and therapeutics in development against MERS-CoV focus on the spike (S) glycoprotein to prevent viral entry into target cells. These efforts, however, are limited by a poor understanding of antibody responses elicited by infection along with their durability, fine specificity and contribution of distinct S antigenic sites to neutralization. To address this knowledge gap, we analyzed S-directed binding and neutralizing antibody titers in plasma collected from individuals infected with MERS-CoV in 2017-2019 (prior to the COVID-19 pandemic). We observed that binding and neutralizing antibodies peak 1 to 6 weeks after symptom onset/hospitalization, persist for at least 6 months, and broadly neutralize human and camel MERS-CoV strains. We show that the MERS-CoV S1 subunit is immunodominant and that antibodies targeting S1, particularly the RBD, account for most plasma neutralizing activity. Antigenic site mapping revealed that polyclonal plasma antibodies frequently target RBD epitopes, particularly a site exposed irrespective of the S trimer conformation, whereas targeting of S2 subunit epitopes is rare, similar to SARS-CoV-2. Our data reveal in unprecedented details the humoral immune responses elicited by MERS-CoV infection, which will guide vaccine and therapeutic design.

Community-Based View on Diagnostic Imaging at the End of COVID-19 Pandemic: Online Survey-Assisted Study (preprint)

Background: Online survey-based observational cross-sectional study aimed at elucidating experience and attitudes of unstructured population regarding diagnostic imaging. Methods: Invitations to participate were distributed using mixed-mode design to deidentified residents aged 18 years and older. Main outcome measures included morbidity structure and incidence of diagnostic imaging administrations. Results: Respondents (n = 1069) aged 44.3 ± 14.4 years; 32.8% suffered from cardiovascular diseases (CVD); 9.5% had chronic respiratory pathology; 28.9% considered themselves healthy. Respondents with COVID-19 history (49.7%) reported higher rates of computed tomography (CT) (p < .0001), magnetic resonance imaging (MRI) (p < .001), and ultrasound (p < .05). COVID-19 history in CVD respondents shifted imaging administrations towards CT and MRI (p < .05). Every tenth respondent received MRI, CT, and ultrasound on paid basis; 29.0% could not pay for diagnostic procedures; 13.1% reported unavailable MRI. Professional status significantly affected the pattern of diagnostic modalities (p < .05). MRI and CT availability differed between respondents in urban and rural areas (p < .0001). History of technogenic events predisposed responders to overestimate diagnostic value of fluorography (p < .05). Conclusions: Preparedness to future pandemics requires development of community-based outreach programs focusing on people's awareness regarding medical imaging safety and diagnostic value.

Unveiling the Lockdown Effects: Exploring Behavior, Dietary Habits and Weight Changes in Rural Egypt during COVID-19 Lockdown: A Cross-Sectional Retrospective Study (preprint)

Background: The COVID-19 lockdown significantly impacted dietary habits and body weights globally, particularly in Egypt, where 57.03% of the population resides in rural areas, despite lack of information. The study examines the impact of COVID-19 lockdown on the weight changes of the rural Egyptian population through behavioral, physical, and dietary changes. Methods: A cross-sectional online survey using Microsoft Forms was distributed in Delta regions in Egypt. The questionnaire used a modified version of the validated 14- items PREDIMED MedDiet Adherence Screener (MEDAS). The first part of the questionnaire addressed sociodemographic variables whereas the second one included questions related to dietary, behavioral and weight changes of participants. These changes were statistically tested for significance in relation to BMI, gender, home living, current job and family history of obesity. Results: A total of 306 participated in the study (70% females, 13% obese, 95% living with family, 56% university students, and 36% with family history of obesity). Obese showed a significant increase in sweet intake whereas underweight and normal weight people displayed a significant decrease in eating desire. Both females and males showed significant increase in consumption of fruits and vegetables with significant decrease in soft drink. However, women showed a significant decrease in sport activity relative to men. Participants living with family showed an increase in sweet intake while those living alone explored an increase in meal frequency. Employers revealed a significant decrease in sport activities and people with family history of obesity reported more sleeping times than those without family history of obesity. Conclusion: During Covid-19 quarantine, Egyptians' eating habits improved, but daily routines were disrupted. Raising awareness about obesity and providing guidance on maintaining activity, energy, and mood is crucial for future quarantine situations.

A Review of Graph Neural Networks in Epidemic Modeling (preprint)

Since the onset of the COVID-19 pandemic, there has been a growing interest in studying epidemiological models. Traditional mechanistic models mathematically describe the transmission mechanisms of infectious diseases. However, they often fall short when confronted with the growing challenges of today. Consequently, Graph Neural Networks (GNNs) have emerged as a progressively popular tool in epidemic research. In this paper, we endeavor to furnish a comprehensive review of GNNs in epidemic tasks and highlight potential future directions. To accomplish this objective, we introduce hierarchical taxonomies for both epidemic tasks and methodologies, offering a trajectory of development within this domain. For epidemic tasks, we establish a taxonomy akin to those typically employed within the epidemic domain. For methodology, we categorize existing work into \textit{Neural Models} and \textit{Hybrid Models}. Following this, we perform an exhaustive and systematic examination of the methodologies, encompassing both the tasks and their technical details. Furthermore, we discuss the limitations of existing methods from diverse perspectives and systematically propose future research directions. This survey aims to bridge literature gaps and promote the progression of this promising field. We hope that it will facilitate synergies between the communities of GNNs and epidemiology, and contribute to their collective progress.

Atomically accurate de novo design of single-domain antibodies (preprint)

Despite the central role that antibodies play in modern medicine, there is currently no way to rationally design novel antibodies to bind a specific epitope on a target. Instead, antibody discovery currently involves time-consuming immunization of an animal or library screening approaches. Here we demonstrate that a fine-tuned RFdiffusion network is capable of designing de novo antibody variable heavy chains (VHH's) that bind user-specified epitopes. We experimentally confirm binders to four disease-relevant epitopes, and the cryo-EM structure of a designed VHH bound to influenza hemagglutinin is nearly identical to the design model both in the configuration of the CDR loops and the overall binding pose.

Evaluation of a rapid test against two ELISAs for a SARS-CoV-2 seroprevalence survey in Kibera informal settlement, Nairobi, Kenya (preprint)

Introduction: The performance of a rapid test was evaluated against two ELISAs as a potentially useful tool to determine exposure to SARS-CoV-2 in low resource settings. A serosurvey was conducted in Kibera informal settlement, Nairobi, Kenya, where low numbers of COVID-19 were recorded during the pandemic. Materials: and methods A cross-sectional study was performed in 10 of 14 villages in Kibera informal settlement, Kenya’s largest slum community, in August 2021, before general vaccine roll-out. Participants were age one year and above with no symptoms of COVID-19. Capillary blood samples were tested using the Standard Q COVID-19 IgM/IgG Combo rapid test, Platelia SARS-CoV-2 Total Ab (IgM/IgG/IgA) Assay, and Wantai Total Ab (IgM/IgG/IgA) ELISA for SARS-CoV-2 which served as the reference test. Results: Samples were obtained from 438 participants; in 72 samples blood was insufficient for the Platelia ELISA. Specificity of the rapid test and Platelia ELISA were similar (>93%) but sensitivity was low (rapid test 61.3%; Platelia ELISA 83.4%). The Wantai ELISA showed greater positivity (82.6%) than the rapid test (51.8%) and Platelia ELISA (69.7%). Conclusions: The Wantai ELISA showed superior performance in this serosurvey. Point-of-care tests for convenient screening for SARS-CoV-2 exposure for surveillance studies need to be developed.

Coxsackievirus A7 and Enterovirus A71 Significally Reduce SARS-CoV-2 Infection in Cell and Animal Models (preprint)

In this study, we investigated the features of co-infection with SARS-CoV-2 and nonpathogenic strain LEV8 of coxsackievirus A7 or enterovirus A71 for Vero E6 cells and Syrian hamsters. The investigation of co-infection with SARS-СoV-2 and LEV-8 or EV-A71 in the cell model was shown that a competitive inhibitory effect for these viruses were especially significant against SARS-CoV-2. Pre-infection with enteroviruses in animals caused more than a 100-fold decrease in the levels of SARS-CoV-2 virus replication in the respiratory tracts and more rapid clearance of the lower respiratory tract from infectious SARS-CoV-2. Co-infection with SARS-CoV-2 and LEV-8 or EV-A71 also reduced the severity of clinical manifestations of the SARS-CoV-2 infection for animals. Additionally, the histological data illustrated that co-infection with nonpathogenic coxsackievirus decreased the level of pathological changes by SARS-CoV-2 in the lungs. Research into the chemokine/cytokine profile demonstrated that the studied enteroviruses efficiently triggered this part of antiviral immune response, which can be associated with significant inhibition of SARS-CoV-2 infection. These results demonstrate that there exists a strong viral interference between the studied nonpathogenic strain of coxsackievirus A7 or enteroviruses A71 and SARS-CoV-2 pathogenic for humans in vitro and in vivo.

Regulation of virion production by the ORF8 signal peptide across SARS-CoV-2 variants (preprint)

The open reading frame 8 (ORF8), an accessory protein of SARS-CoV-2, is prone to deletions and mutations across different viral variants, which was first described in several Singapore variants. The reason why viral evolution favors loss or inactivation of ORF8 is not fully understood, although the effects of ORF8 on inflammation, immune evasion, and disease severity have been described. Here we show using clinical ORF8 deficient viral isolates, virus like particles (VLPs) and viral replicons that ORF8 expression dampens viral particle production. ORF8 physically interacts with the viral Spike protein and induces Golgi fragmentation, overall contributing to less virus particle production. Using systematic ORF8 deletions, we mapped the particle reducing function to its N terminal signal peptide. Interestingly, this part of ORF8 is severely truncated in the recent XBB.1.5 variant, and when restored, suppresses viral particle production in the context of the entire viral genome. Collectively, our data support the model that evolutionary pressure exists to delete ORF8 sequence and expression across SARS-CoV-2 variants to fully enable viral particle production.

Programming the scalable optical learning operator with spatial-spectral optimization (preprint)

Electronic computers have evolved drastically over the past years with an ever-growing demand for improved performance. However, the transfer of information from memory and high energy consumption have emerged as issues that require solutions. Optical techniques are considered promising solutions to these problems with higher speed than their electronic counterparts and with reduced energy consumption. Here, we use the optical reservoir computing framework we have previously described (Scalable Optical Learning Operator or SOLO) to program the spatial-spectral output of the light after nonlinear propagation in a multimode fiber. The novelty in the current paper is that the system is programmed through an output sampling scheme, similar to that used in hyperspectral imaging in astronomy. Linear and nonlinear computations are performed by light in the multimode fiber and the high dimensional spatial-spectral information at the fiber output is optically programmed before it reaches the camera. We then used a digital computer to classify the programmed output of the multi-mode fiber using a simple, single layer network. When combining front-end programming and the proposed spatial-spectral programming, we were able to achieve 89.9% classification accuracy on the dataset consisting of chest X-ray images from COVID-19 patients. At the same time, we obtained a decrease of 99% in the number of tunable parameters compared to an equivalently performing digital neural network. These results show that the performance of programmed SOLO is comparable with cutting-edge electronic computing platforms, albeit with a much-reduced number of electronic operations.

SARS-CoV-2 diversity and transmission on a university campus across two academic years during the pandemic (preprint)

Institutions of higher education (IHEs) have been a focus of SARS-CoV-2 transmission studies but there is limited information on how viral diversity and transmission at IHEs changed as the pandemic progressed. Here we analyze 3606 viral genomes from unique COVID-19 episodes collected at a public university in Seattle, Washington (WA) from September 2020 to September 2022. Across the study period, we found evidence of frequent viral transmission among university affiliates with 60% (n=2153) of viral genomes from campus specimens genetically identical to at least one other campus specimen. Moreover, viruses from students were observed in transmission clusters at a higher frequency than in the overall dataset while viruses from symptomatic infections were observed in transmission clusters at a lower frequency. Though only a small percentage of community viruses were identified as possible descendants of viruses isolated in university study specimens, phylodynamic modelling suggested a high rate of transmission events from campus into the local community, particularly during the 2021-2022 academic year. We conclude that viral transmission was common within the university population throughout the study period but that not all university affiliates were equally likely to be involved. In addition, the transmission rate from campus into the surrounding community may have increased during the second year of the study, possibly due to return to in-person instruction.

The S2 subunit of spike encodes diverse targets for functional antibody responses to SARS-CoV-2 (preprint)

The SARS-CoV-2 virus responsible for the COVID-19 global pandemic has exhibited a striking capacity for viral evolution that drives continued evasion from vaccine and infection-induced immune responses. Mutations in the receptor binding domain of the S1 subunit of the spike glycoprotein have led to considerable escape from antibody responses, reducing the efficacy of vaccines and monoclonal antibody (mAb) therapies. Therefore, there is a need to interrogate more constrained regions of Spike, such as the S2 subdomain. Here, we describe a collection of S2 mAbs from two SARS-CoV-2 convalescent individuals that target multiple regions in the S2 subdomain and can be grouped into at least five epitope classes. Most did not neutralize SARS-CoV-2 with the exception of C20.119, which bound to a highly conserved epitope in the fusion peptide and showed broad binding and neutralization activity across SARS-CoV-2, SARS-CoV-1, and closely related zoonotic sarbecoviruses. Several of the S2 mAbs tested mediated antibody-dependent cellular cytotoxicity (ADCC) at levels similar to the S1 mAb S309 that was previously authorized for treatment of SARS-CoV-2 infections. Three of the mAbs with ADCC function also bound to spike trimers from HCoVs, such as MERS-CoV and HCoV-HKU1. Our findings suggest there are diverse epitopes in S2, including functional S2 mAbs with HCoV and sarbecovirus breadth that likely target functionally constrained regions of spike. These mAbs could be developed for potential future pandemics, while also providing insight into ideal epitopes for eliciting a broad HCoV response.

Factors Associated with Changes in Reproductive Outcomes during the first year of COVID- 19 pandemic in Burkina Faso: A multinomial analysis from a longitudinal study using PMA 2030 data (preprint)

Background:The advent of COVID-19 pandemic has dramatically affected women’s life and livelihoods. In the past decade, the promotion of family planning contributed to reduced poverty and averted poor maternal and child outcomes. There is evidence that these gains may be threatened by social restrictions following COVID-19 outbreak. Methods:We used data from a longitudinal survey collected by the Performance Monitoring Accountability in Burkina Faso. Data were collected over one-year period, from before (November 2019–February 2020) and during (November 2020–February 2021) COVID-19 pandemic. We evaluate changes in reproductive outcomes with respect to changes in health and economic circumstances as well as sociodemographic conditions among 1372 women aged 15-49 at risk of pregnancy and potential contraceptive users. Bivariate and multivariate multinomial logistic regression were performed to examine correlates of reproductive outcomes. Results:Half (52%) of women did not change their reproductive status. While, 29% had childbearing, 19% started using a contraceptive method. In the multivariate analysis, childbearing was relatively higher among women exposed to family planning promotion, healthcare utilization, but relatively lower among those employed without cash paid and those who experienced household income loss. As of contraception, women exposed to family planning promotion were also associated with a relatively higher contraceptive use while concerns about getting COVID-19 infection had the opposite effect. Conclusion:After a year period of COVID-19 outbreak, contraceptive adoption increased significantly, but at a slower pace which was not enough to reduce childbearing. The most vulnerable women may remain at greater risk of unintended pregnancies and poor maternal and child outcomes. Therefore, family planning programs should direct their efforts into combatting misinformation and reaching out women in communities in the context of COVID-19 restrictions.

Cross-neutralizing antibody against emerging Omicron subvariants of SARS-CoV-2 in infection-naïve individuals with homologous BNT162b2 or BNT162b2(WT+ BA.4/5) bivalent booster vaccination (preprint)

Since the emergence of SARS-CoV-2, different variants and subvariants successively emerged to dominate global virus circulation as a result of immune evasion, replication fitness or both. COVID-19 vaccines continue to be updated in response to the emergence of antigenically divergent viruses, the first being the bivalent RNA vaccines that encodes for both the Wuhan-like and Omicron BA.5 subvariant spike proteins. Repeated infections and vaccine breakthrough infections have led to complex immune landscapes in populations making it increasingly difficult to assess the intrinsic neutralizing antibody responses elicited by the vaccines. Hong Kong’s intensive COVID-19 containment policy through 2020–2021 permitted us to identify sera from a small number of infection naïve individuals who received 3 doses RNA vaccine BNT162b2 of vaccines encoding the Wuhan-like spike who were boosted with a fourth dose monovalent Wuhan-like (WT) vaccine or the bivalent Wuhan-like and BA.4/5 spike (WT + BA.4/5) expressing vaccine. While neutralizing antibody to wild-type virus was comparable in both vaccine groups, BNT162b2 bivalent vaccine elicited significantly higher plaque neutralizing antibodies to Omicron subvariants BA.5, XBB.1.5, XBB.1.16, XBB.1.9.1, XBB.2.3.2, EG.5.1, HK.3, BA.2.86 and JN.1, compared to BNT162b2 monovalent vaccine. The single amino acid substitution that differentiates the spike of JN.1 from BA.2.86 resulted in a profound antigenic change.

Provider and community perspectives of integrated COVID-19 and routine childhood immunisation programmes in Nigeria: a qualitative exploratory study (preprint)

Background In Nigeria, COVID-19 vaccines were delivered through outreach activities and integrated with routine immunisation. However, evaluations of integrated approaches for novel vaccines are scarce. We aimed to understand the perceived benefits and challenges of integrating the COVID-19 vaccine within routine- immunisation in Nigeria and identify ways to strengthen this approach.Methods We conducted 30 semi-structured interviews with community members and healthcare workers in primary healthcare (PHC) facilities in Jigawa (n = 16) and Oyo (n = 14) states, Nigeria in August 2022. Participants were selected purposively from PHC facilities. Healthcare worker and community interviews were analysed separately using thematic analysis.Results We identified four themes that describe the community response, perceived impact, and health system adaptions to the challenges associated with the integrated vaccine delivery approach. Community members expressed concern that children might be given COVID-19 vaccines instead of routine immunisations, while others appreciated the integrated approach due to their trust in the efficacy of COVID-19 vaccines, government, and healthcare providers. Healthcare providers perceived the integrated approach as improving vaccination coverage and awareness but noted additional problems of increased workload, vaccine scarcity, and prolonged clinic visits. Insufficient resources were subsisting barriers to effective integration in both states, but the provider’s gender was also a challenge in Jigawa state. Additionally, the use of incentives to generate demand had ambiguous effects in Jigawa state.Conclusion Taking an integrated approach to deliver COVID-19 vaccines was acceptable by health workers but resisted from the community. Addressing persistent challenges in existing vaccination programmes is pertinent to enhance effectiveness and acceptability of the integrated approach.

Long-term cardiovascular safety of COVID-19 vaccination according to brand, dose and combinations: Cohort study of 46 million adults in England (preprint)

Using longitudinal health records from 45.7 million adults in England followed for a year, our study compared the incidence of thrombotic and cardiovascular complications after first, second and booster doses of brands and combinations of COVID-19 vaccines used during the first two years of the UK vaccination program with the incidence before or without the corresponding vaccination. The incidence of common arterial thrombotic events (mainly acute myocardial infarction and ischaemic stroke) was generally lower after each vaccine dose, brand and combination. Similarly, the incidence of common venous thrombotic events, (mainly pulmonary embolism and lower limb deep venous thrombosis) was lower after vaccination. There was a higher incidence of previously reported rare harms after vaccination: vaccine-induced thrombotic thrombocytopenia after first ChAdOx1 vaccination, and myocarditis and pericarditis after first, second and transiently after booster mRNA vaccination (BNT-162b2 and mRNA- 1273) These findings support the wide uptake of future COVID-19 vaccination programs.